Anaplastic lymphoma kinase (ALK) is a member of receptor tyrosine kinase family, which can recruit downstream protein by autophosphorylation, and further modulate cell metabolism and growth by expression of a specific gene. Anaplastic lymphoma kinase was first found in Anaplastic large cell lymphoma (ALCL), and was also found later to be expressed in a high level in non-small cell lung cancer (NSCLC).
The abnormal expression of ALK in some ALCL/NSCLC was resulted from different chromosomal translocations. These chromosomal translocations may result in the production of the corresponding fusion proteins. The analysis of these fusion genes shows that they all comprise a 3′ terminal gene sequence of ALK gene, which encodes an intracellular kinase domain; and the gene fragments fused to ALK all comprise a promoter element and encode a sequence that mediates self-dimerization, thus resulting in high expression and over-activation of the fusion protein having ALK kinase activity, and causing malignant transformation of cell. Therefore, the activity of intracellular kinase domain of ALK and the corresponding signal transduction pathway are the important molecular mechanism responsible for the development of ALCL. In addition to ALK, ROS1 is another hot target gene studied in lung adenocarcinoma. ROS1 is a member of receptor tyrosine kinase family. ROS1 is responsible for an incidence rate of about 1.7% for NSCLC. ROS1 and Anaplastic lymphoma kinase (ALK) have a homology of 49% in kinase domain, and have an identity of 77% in ATP-binding site, which makes the treatment of NSCLC with ROS1 rearrangement by using ALK kinase inhibitor possible.
Therefore, the development of small molecular inhibitors against ALK/ROS1 may effectively reduce the effect of the mutated ALK/ROS1 gene on downstream proteins, thereby influencing invasion and proliferation of tumor cells, and the like, and finally influencing the growth of tumor cells and exerting anti-tumor effect. Crizotinib developed by Pfizer has come into the market successfully now, and has been widely accepted as it has good therapeutic effect against EML4-ALK mutated non-small cell lung cancer. With the appearance of Crizotinib on the market, specific diagnostic kits have also come into market. Before the application of a medicament, a patient is diagnosed by a kit to determine whether he or she has ALK mutation. For specific patients, ALK inhibitors exhibit good inhibitory activity. The research on Crizotinib against ROS1 has been in the clinic stage, and achieved a breakthrough role in pharmacotherapy. However, there are a lot of clinical trials showing that patients having ALK fusion generally exhibit resistance to Crizotinib after 1-2 years treatment. The mechanism underlying the generation of resistance to Crizotinib is very complex, wherein ALK mutation is responsible for about ⅓ of resistance cases, and the mutation sites mainly include L1196M, C1156Y, F1174L, etc. Therefore, it is of great clinical significance to design and screen the second generation ALK inhibitors having good therapeutic effect in patients resistant to Crizotinib.
The second generation ALK inhibitors, which have come into the market now, include Ceritinib from Novartis, and Alectinib from Chugai Pharmaceutical Co. Ltd. under Roche; and the ALK inhibitors in clinical stage include AZD-3463, AP26113, etc.

Therefore, it is of great significance for the treatment of diseases caused by ALK mutation in clinic to look for new small molecular compounds having excellent inhibitory activity against ALK fusion and drug resistant mutations by modifying a compound structure, make great efforts to improve physico-chemical properties of compounds, and enhance druggability, such as bioavailability of compounds.
Contents of Invention
In order to develop small molecular inhibitors against ALK, Examples of the invention provide a polycyclic inhibitor of anaplastic lymphoma kinase having good effect on the treatment and/or prevention of an ALK-mediated cancer or non-cancer related disease. The technical solutions are as follows:
Solution 1. A Compound of Formula (I), or a Pharmaceutically Acceptable Salt or Stereoisomer Thereof:

wherein,
R1 is selected from the group consisting of —COR5, —CO2R5, —CONRR5, —SOR5, —SO2R5 and —SO2NRR5;
R2 is selected from the group consisting of hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6alkyl, hydroxyC1-6alkyl, halo-C1-6alkyl, aminoC1-6alkyl, C1-6alkoxy, hydroxyC1-6alkoxy, halo-C1-6alkoxy, C2-8alkenyl, C2-8alkynyl, C1-6alkylthio, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylsulfonamido, C1-6alkylaminosulfonyl, (C1-6alkyl)2aminosulfonyl and C1-6alkylsulfonyl;
R3 is selected from the group consisting of 5-14 membered heteroaryl optionally substituted with 1-3 substituent(s) W, and 3-8 membered heterocyclyl optionally substituted with 1-3 substituent(s) W,
W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, (C1-6alkyl)2amino, halo-C1-6alkyl, halo-C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylsulfonyl, C2-8alkenyl and C2-8alkynyl;
R4 is selected from the group consisting of hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-6alkoxy, 3-8 membered carbon ring-O—, C1-6alkyl, hydroxyC1-6alkyl, halo-C1-6alkyl, hydroxyC1-6alkoxy, halo-C1-6alkoxy, C2-8alkenyl, C2-8alkynyl, C1-6alkylamino, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy and (C1-6alkyl)2amino;
R and R5 are independently selected from the group consisting of hydrogen atom, C1-6alkyl and 3-8 membered carbon ring;
A is selected from the group consisting of 3-8 membered cycloalkyl optionally substituted with substituent Q, 4-5 membered heterocyclyl containing two O, S and/or N atoms that is optionally substituted with substituent Q, and 6-8 membered heterocyclyl containing 1-2 O, S and/or N atom(s) that is optionally substituted with substituent Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, (C1-6alkyl)2amino, halo-C1-6alkyl, halo-C1-6alkoxy, C1-6alkoxyC1-6alkyl, C2-8alkenyl, C2-8alkynyl and 3-8 membered heterocyclyl.
Solution 2. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 1,
wherein,
R1 is selected from the group consisting of —CO2R5, —CONRR5, —SO2R5 and —SO2NRR5;
R2 is selected from the group consisting of hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6alkyl, hydroxyC1-6alkyl and halo-C1-6alkyl;
R3 is selected from the group consisting of 5-8 membered heteroaryl containing 1-2 O, S and/or N atom(s) that is optionally substituted with 1-2 substituent(s) W, and 4-6 membered heterocyclyl containing 1-2 O, S and/or N atom(s) that is optionally substituted with 1-2 substituent(s) W,
W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, (C1-6alkyl)2amino, halo-C1-6alkyl, halo-C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy, C1-6alkylsulfonyl, C2-8alkenyl and C2-8alkynyl;
R4 is selected from the group consisting of hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-6alkoxy, C1-6alkyl, hydroxyC1-6alkyl, halo-C1-6alkyl, hydroxyC1-6alkoxy, halo-C1-6alkoxy, C1-6alkylamino, C1-6alkylcarbonyl and C1-6alkylcarbonyloxy;
R and R5 are independently selected from the group consisting of hydrogen atom, C1-6alkyl and 5-6 membered saturated or partially saturated carbon ring;
A is selected from the group consisting of 5-6 membered cycloalkyl optionally substituted with substituent Q, 4-5 membered heterocyclyl containing two O, S and/or N atoms that is optionally substituted with substituent Q, and 6-7 membered heterocyclyl containing 1-2 O, S and/or N atom(s) that is optionally substituted with substituent Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-6alkyl.
Solution 3. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 2,
wherein,
R1 is selected from the group consisting of —SO2R5 and —SO2NRR5;
R2 is selected from the group consisting of hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl and C1-6alkyl;
R3 is selected from the group consisting of 5-6 membered heteroaryl containing 1-2 N atom(s) that is optionally substituted with 1-2 substituent(s) W, and 4-6 membered heterocyclyl containing 1-2 N atom(s) that is optionally substituted with 1-2 substituent(s) W,
W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, (C1-6alkyl)2amino, halo-C1-6alkyl, halo-C1-6alkoxy, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy and C1-6alkylsulfonyl;
R4 is selected from the group consisting of hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-6alkoxy, C1-6alkyl, halo-C1-6alkyl, C1-6alkylamino, C1-6alkylcarbonyl and C1-6alkylcarbonyloxy;
R and R5 are independently selected from the group consisting of hydrogen atom and C1-6alkyl;
A is selected from the group consisting of 5 membered heterocyclyl containing two O, S and/or N atoms that is optionally substituted with 1-2 substituent(s) Q, and 6 membered heterocyclyl containing 1-2 O, S and/or N atom(s) that is optionally substituted with 1-2 substituent(s) Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-6alkyl.
Solution 4. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 3,
wherein,
R1 is selected from the group consisting of —SO2R5 and —SO2NRR5;
R2 is selected from the group consisting of hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl and C1-6alkyl;
R3 is selected from 4-6 membered heterocyclyl containing 1-2 N atom(s) that is optionally substituted with 1-2 substituent(s) W;
W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4alkyl, C1-4alkoxy, C1-4alkylamino, (C1-4alkyl)2amino, halo-C1-4alkyl, halo-C1-4alkoxy, C1-4alkylcarbonyl, C1-4alkylcarbonyloxy and C1-4alkylsulfonyl;
R4 is selected from the group consisting of fluorine atom, bromine atom and chlorine atom;
R and R5 are independently selected from C1-4alkyl;
A is selected from the group consisting of 5 membered heterocyclyl containing two O, S and/or N atoms and 6 membered heterocyclyl containing 1-2 O, S and/or N atom(s), optionally substituted with one substituent Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-4alkyl.
Solution 5. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 3,
wherein,
R1 is selected from the group consisting of —SO2R5 and —SO2NRR5;
R2 is selected from the group consisting of hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl and C1-4alkyl;
R3 is selected from the group consisting of pyridinyl, dihydropyridinyl, tetrahydropyridinyl, azetidinyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, pyrazolyl, dihydropyrazolyl, tetrahydropyrazolyl, imidazolyl, dihydroimidazolyl, tetrahydroimidazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, piperidyl, piperazinyl and morpholinyl;
R4 is selected from the group consisting of fluorine atom, bromine atom and chlorine atom;
R and R5 are independently selected from C1-4alkyl;
A is selected from the group consisting of 5 membered heterocyclyl containing two oxygen atoms and 6 membered heterocyclyl containing 1-2 oxygen atom(s), optionally substituted with one substituent Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-4alkyl.
Solution 6. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 5,
wherein,
R1 is selected from the group consisting of —SO2R5 and —SO2NRR5;
R2 is selected from the group consisting of hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl;
R3 is selected from the group consisting of pyridinyl, dihydropyridinyl, tetrahydropyridinyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, azetidinyl, piperidyl, piperazinyl and morpholinyl;
R4 is selected from the group consisting of fluorine atom, bromine atom and chlorine atom;
R and R5 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl;
A is selected from 6 membered heterocyclyl containing two oxygen atoms that is optionally substituted with one substituent Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
Solution 7. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 5,
wherein,
R3 is selected from the group consisting of tetrahydropyridinyl, azetidinyl, tetrahydropyrrolyl, tetrahydropyrazolyl, tetrahydroimidazolyl, tetrahydropyrimidinyl, piperidyl, piperazinyl and morpholinyl;
A is selected from 5 membered heterocyclyl containing two oxygen atoms that is optionally substituted with one substituent Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-4alkyl.
Solution 8. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 5,
wherein,
R3 is selected from the group consisting of tetrahydropyridinyl, azetidinyl, tetrahydropyrrolyl, pyrazolyl, tetrahydroimidazolyl, tetrahydropyrimidinyl, piperidyl, piperazinyl and morpholinyl;
A is selected from 6 membered heterocyclyl containing two oxygen atoms that is optionally substituted with one substituent Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-4alkyl.
Solution 9. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 5,
wherein,
R3 is selected from the group consisting of pyridinyl, dihydropyridinyl, tetrahydropyridinyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, azetidinyl, piperidyl, piperazinyl and morpholinyl;
A is selected from 6 membered heterocyclyl containing one oxygen atom, optionally substituted with one substituent Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-4alkyl.
Solution 10. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 3,
wherein,
R3 is selected from 4-6 membered partially saturated heterocyclyl containing 1-2 nitrogen atom(s) that is optionally substituted with 1-2 substituent(s) W, and R3 is linked to phenyl via carbon atom;
W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, (C1-6alkyl)2amino, halo-C1-6alkyl, halo-C1-6alkoxy, C1-6alkylcarbonyl, C1-6alkylcarbonyloxy and C1-6alkylsulfonyl;
A is selected from 6 membered heterocyclyl containing one O, S and/or N atom, optionally substituted with 1-2 substituent(s) Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-6alkyl.
Solution 11. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 3,
wherein,
R1 is selected from the group consisting of —SO2R5 and —SO2NRR5;
R2 is selected from the group consisting of hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl and C1-6alkyl;
R3 is selected from 4-6 membered saturated heterocyclyl containing 1-2 N atom(s) that is optionally substituted with 1-2 substituent(s) W, and R3 is linked to phenyl via carbon atom;
W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6alkyl, C1-6alkoxy and C1-6alkylamino;
R4 is selected from the group consisting of hydrogen atom, halogen atom, cyano, nitro, amino, hydroxyl, carboxyl, C1-6alkoxy and C1-6alkyl;
R and R5 are independently selected from the group consisting of hydrogen atom and C1-6alkyl;
A is selected from the group consisting of 5 membered heterocyclyl containing two oxygen atoms that is optionally substituted with 1-2 substituent(s) Q, and 6 membered heterocyclyl containing 1-2 oxygen atom(s) that is optionally substituted with 1-2 substituent(s) Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-6alkyl.
Solution 12. The Compound, or the Pharmaceutically Acceptable Salt or Stereoisomer Thereof According to Solution 3,
wherein,
R1 is selected from the group consisting of —SO2R5 and —SO2NRR5;
R2 is selected from the group consisting of hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl and C1-4alkyl;
R3 is selected from the group consisting of pyridinyl, dihydropyridinyl, tetrahydropyridinyl, azetidinyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, piperidyl, piperazinyl and morpholinyl;
R4 is selected from the group consisting of fluorine atom, bromine atom and chlorine atom;
R and R5 are independently selected from C1-4alkyl;
A is selected from 5 membered heterocyclyl containing two N atoms and 6 membered heterocyclyl containing 1-2 N atom(s), optionally substituted with 1-2 substituent(s) Q; the substituent Q is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom and C1-4alkyl.
A Part of Compounds of the Invention
No.Structural formula1 2 3 4 5 6 7 8 9 10